Topic 18: Opioid Reinforcement and Dependence

Question 1

How are the reinforcing effects of opioids demonstrated in animal models?

Answer 1

animals readily acquire operant self-administration of opiates

self-administration increases over time to a stable total level - seperate pretreatment with morphine will decrease self-administration to reach the same approximate levels

animals readily develop conditioned place preference for opiate use

Question 2

What is the course of heroin self-administration in animal models?

Answer 2

heroin self-administration reaches steady-state levels and are self-regulated by rats

heroin SA contrasts sharply with cocaine SA in which use is erratic and subject mortality is high

Question 3

What is the mesolimbic dopamine pathway?

Answer 3

opioids function within the mesolimbic dopamine reward pathway

dopaminergic projections from the VTA project to the nucleus accumbens providing motivational salience to information passing to the ventral palladium

in the absence of reinforcing stimuli DA release is under tonic inhibitory control of GABA interneurons

dopamine release in the NAc provides a positive reinforcement to associated behaviors

Question 4

How do opioids function within the mesolimbic dopamine pathway?

Answer 4

endorphin-secreting neurons provide inhibitory input to GABAergic interneurons in the VTA

endorphin release or MOR activation results in disinhibition of NAc DA release

beta-endorphin provides inhibitory control over GABA neurons

mu-receptor activation results in disinhibition of NAc DA release

opiates act at GABAergic interneuron terminals (axoaxonal transmission) to disinhibit NAc dopamine release and increase motivational salience

dynorphin provides direct inhibitory control over DA neurons

kappa-receptor activation results in inhibition of NAc DA release

Question 5

What are the reinforcing effects of opioid receptor agonists?

Answer 5

agonists at mu and delta receptors are reinforcing and readily lead to self-administration and conditioned place preference (CPP)

agonists at the kappa receptors do not acquire self-administration and will actually induce conditioned place aversion

endogenous opioids provide salience through mesolimbic DA modulation

opiates act principally through mu-opioid receptors to provide incentive salience

dynorphins act through kappa-opioid receptors to provide aversive salience

dopamine lesion using 6-OHDA reduces but does not abolish opiate self-administration

Question 6

How does reinforcement play a role in opioid addiction?

Answer 6

opiates and other drugs of abuse are considered to engage natural reward circuitry in a manner that bypass the need for sensory input/processing

relative intensity of reinforcement is thought to relate to the more direct coupling of drug administration with activation of reward circuitry

reinforcement increases with different routes of administration

in human reinforcement by drugs of abuse is though to be far stronger than natural rewards: reduced self-care is common among drug users, including poor or insufficient diet

Question 7

How does opioid reinforcement increase with different routes of administration?

Answer 7

heroin is more reinforcing than morphine due to more rapid transit across the BBB

IV administration is more reinforcing than oral or IM administration due to more rapid across to the BBB

drugs available by inhalation (especially nicotine) have very rapid access to the brain and are highly rewarding

Question 8

What is rebound hyperactivity?

Answer 8

as opiates are depressants their withdrawal results in CNS hyperactivity

withdrawal symptoms can be described as rebound hyperactivity as neural circuits operate as a disturbed homeostatic level

withdrawal effects contrast/oppose acute effects of intoxication

Question 9

What are acute effects of opioids and their associated rebound withdrawal symptoms?

Answer 9

analgesia –> pain and irritability

euphoria –> dysphoria and depression

relaxation and sleep –> restlessness and insomnia

constipation –> diarrhea

pupil constriction –> pupil dilation

flushed and warm skin –> chilliness and goosebumbs

Question 10

How is learning and memory involved in tolerance and dependence?

Answer 10

in humans behavioral tolerance contributes to the decreased effects of opiates

tolerance and dependence are reversible adaptive changes to drug use

learning and memory processes can be demonstrated to contribute to tolerance in animal models

NMDA receptor antagonists (MK801) reduce tolerance to analgesia as measured by tail-flick latency

Question 11

What is the physical dependence model of drug addiction?

Answer 11

establishment and maintenance of addictions manifests from development of dependence

abstinence (withdrawal) results in craving, leading to relapse

posits addiction is a result of negative feedback in trying to eliminate unpleasantness of abstinence

role of classical conditioning in craving and relapse: conditioning of withdrawal symptoms

Question 12

What are the limitations of the physical dependence model?

Answer 12

addiction results from physical dependence: some addictive drugs do not demonstrate dependence, dependence can be demonstrated without addiction, dependence only explains persistent use, not initial use

relapse results from withdrawal: relapse can occur well after detoxification, role of classical conditioning in relapse is not well demonstrated in humans - mostly anecdotal evidence

model fails to account for psychological contributions to relapse and craving

Question 13

What is the positive reinforcement model of addiction?

Answer 13

drug addiction results from positive feedback - compulsive desire to experience drug-related euphoria

well demonstrated in animal models of self-administration

euphoria resulting from initial drug use serves to reinforce additional use

Question 14

What are the limitations of the positive reinforcement model?

Answer 14

craving increases with prolonged use: euphoric effects tend to diminish with use due to tolerance

many users voluntarily stop using drugs that are strongly reinforcing like cocaine and heroin, individual differences in susceptibility to addictions is not explained by the reinforcing effects of drug-induced euphoria

Question 15

What is the incentive-sensitization model of addiction?

Answer 15

distinguishes drug liking (drug “high”) and drug wanting (craving)

increased use occurs with increased wanting even though drug liking remains the same or decreases

proposes two distinct underlying neurobiological processes for liking and wanting

drug wanting system undergoes sensitization: mesolimbic DA system readily sensitized

drug liking system undergoes tolerance

changes in incentive salience process can be long-lasting

Question 16

What is the opponent-process model of addiction?

Answer 16

affective processes responsive to strong stimuli (e.g., euphoria) are balanced by opposing affective responses that is experienced after initial response ends

affective stimuli would be the “high”, opponent process would be withdrawal

repeat presentation of strong stimuli results in strengthening of the opponent process

adaptive processes lower hedonic set point such that chronic users experience dysphoria in the absence of drugs

Question 17

What are the limitations of the incentive-sensitization and opponent-process model?

Answer 17

both address neural mechanisms of drug abuse

both explain different aspects of addiction

neither model addresses initial drug use

limited incorporation of psychosocial factors contributing to addictive pattern of use

Question 18

What are the disease models of addiction?

Answer 18

propose that drug addiction results from inherent differences in susceptibility: exposure to drug in some individuals results in loss of control over intake, most widely accepted for alcoholism

alternate explanation is that drug exposure alters brain function leading to loss of control

drug use initiation is necessary but not sufficient for development of a substance-use disorder

disinhibition (predisposition to impulsivity, hyperactivity, antisociality) is predictive risk of substance-use (regardless of the substance)

disease model removes the moral aspects of addictions